Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition

Rahul Bharadwaj; Cyril J. Peter; Yan Jiang; Panos Roussos; Annie Vogel-Ciernia; Erica Y. Shen; Amanda C. Mitchell; Wenjie Mao; Catheryne Whittle; Aslihan Dincer; Mira Jakovcevski; Venu Pothula; Theodore P. Rasmussen; Stella G. Giakoumaki; Panos Bitsios; Ajfar Sherif; Paul D. Gardner; Patricia Ernst; Subroto Ghose; Pamela Sklar; Vahram Haroutunian; Carol Tamminga; Richard H. Myers; Kensuke Futai; Marcelo A. Wood; Schahram Akbarian

doi:10.1016/j.neuron.2014.10.032

Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition

Rahul Bharadwaj, Cyril J. Peter, Yan Jiang, Panos Roussos, Annie Vogel-Ciernia, Erica Y. Shen, Amanda C. Mitchell, Wenjie Mao, Catheryne Whittle, Aslihan Dincer, Mira Jakovcevski, Venu Pothula, Theodore P. Rasmussen, Stella G. Giakoumaki, Panos Bitsios, Ajfar Sherif, Paul D. Gardner, Patricia Ernst, Subroto Ghose, Pamela SklarVahram Haroutunian, Carol Tamminga, Richard H. Myers, Kensuke Futai, Marcelo A. Wood, Schahram Akbarian

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

Three-dimensional chromosomal conformations regulate transcription by moving enhancers and regulatory elements into spatial proximity with target genes. Here we describe activity-regulated long-range loopings bypassing up to 0.5 Mb of linear genome to modulate NMDA glutamate receptor GRIN2B expression in human and mouse prefrontal cortex. Distal intronic and 3' intergenic loop formations competed with repressor elements to access promoter-proximal sequences, and facilitated expression via a "cargo" of AP-1 and NRF-1 transcription factors and TALE-based transcriptional activators. Neuronal deletion or overexpression of Kmt2a/Mll1 H3K4- and Kmt1e/Setdb1 H3K9-methyltransferase was associated with higher-order chromatin changes at distal regulatory Grin2b sequences and impairments in working memory. Genetic polymorphisms and isogenic deletions of loop-bound sequences conferred liability for cognitive performance and decreased GRIN2B expression. Dynamic regulation of chromosomal conformations emerges as a novel layer for transcriptional mechanisms impacting neuronal signaling and cognition.

Original language	English (US)
Pages (from-to)	997-1008
Number of pages	12
Journal	Neuron
Volume	84
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2014.10.032
State	Published - Dec 3 2014

ASJC Scopus subject areas

General Neuroscience

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Bharadwaj, R., Peter, C. J., Jiang, Y., Roussos, P., Vogel-Ciernia, A., Shen, E. Y., Mitchell, A. C., Mao, W., Whittle, C., Dincer, A., Jakovcevski, M., Pothula, V., Rasmussen, T. P., Giakoumaki, S. G., Bitsios, P., Sherif, A., Gardner, P. D., Ernst, P., Ghose, S., ... Akbarian, S. (2014). Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition. Neuron, 84(5), 997-1008. https://doi.org/10.1016/j.neuron.2014.10.032

Bharadwaj, R, Peter, CJ, Jiang, Y, Roussos, P, Vogel-Ciernia, A, Shen, EY, Mitchell, AC, Mao, W, Whittle, C, Dincer, A, Jakovcevski, M, Pothula, V, Rasmussen, TP, Giakoumaki, SG, Bitsios, P, Sherif, A, Gardner, PD, Ernst, P, Ghose, S, Sklar, P, Haroutunian, V, Tamminga, C, Myers, RH, Futai, K, Wood, MA & Akbarian, S 2014, 'Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition', Neuron, vol. 84, no. 5, pp. 997-1008. https://doi.org/10.1016/j.neuron.2014.10.032

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abstract = "Three-dimensional chromosomal conformations regulate transcription by moving enhancers and regulatory elements into spatial proximity with target genes. Here we describe activity-regulated long-range loopings bypassing up to 0.5 Mb of linear genome to modulate NMDA glutamate receptor GRIN2B expression in human and mouse prefrontal cortex. Distal intronic and 3' intergenic loop formations competed with repressor elements to access promoter-proximal sequences, and facilitated expression via a {"}cargo{"} of AP-1 and NRF-1 transcription factors and TALE-based transcriptional activators. Neuronal deletion or overexpression of Kmt2a/Mll1 H3K4- and Kmt1e/Setdb1 H3K9-methyltransferase was associated with higher-order chromatin changes at distal regulatory Grin2b sequences and impairments in working memory. Genetic polymorphisms and isogenic deletions of loop-bound sequences conferred liability for cognitive performance and decreased GRIN2B expression. Dynamic regulation of chromosomal conformations emerges as a novel layer for transcriptional mechanisms impacting neuronal signaling and cognition.",

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AU - Shen, Erica Y.

AU - Mitchell, Amanda C.

AU - Mao, Wenjie

AU - Whittle, Catheryne

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AU - Jakovcevski, Mira

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AU - Rasmussen, Theodore P.

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AU - Bitsios, Panos

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AU - Gardner, Paul D.

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AU - Ghose, Subroto

AU - Sklar, Pamela

AU - Haroutunian, Vahram

AU - Tamminga, Carol

AU - Myers, Richard H.

AU - Futai, Kensuke

AU - Wood, Marcelo A.

AU - Akbarian, Schahram

PY - 2014/12/3

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Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition

Abstract

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